Many drugs have unfavorable physicochemical properties which create barriers to the attainment of their maximum therapeutic potential. The creation of prodrugs provides a means of chemically modifying drugs in order to temporarily modify the drugs' physicochemical properties. The prodrug is then able to overcome the original barrier, revert back to the parent drug, interact with the receptor and elicit a pharmacological response at the drug's site of action (FIG. 1).
Secondary and tertiary amines often have reasonable aqueous solubility at low pH values but tend to be insoluble around the physiological pH values. Traditional methods for formulating parental dosage forms of tertiary amines have involved non-physiological pH conditions (low pH) and/or exotic, non-aqueous co-solvent addition as well as the use of cyclodextrins and detergents. These traditional methods often have secondary toxicities associated with them which are not observed with the parent drug alone.
Tertiary amines are unusual in chat their derivatization forms quaternary ammonium compounds. However, quaternary salts resulting from simple alkylation of tertiary amines are very stable and do not easily revert back to the parent tertiary amine, thereby limiting their suitability as prodrugs. In addition, if they are used as prodrugs, quaternary ammonium compounds can be quite toxic, therefore the requirement for rapid conversion to the parent tertiary amine is essential. Bodor (U.S. Pat. No. 4,160,099; U.S. Pat. No. 4,254,765; U.S. Pat. No. 4,061,722; Bodot, N. 1981; Bodor, N. et al., 1980(a); Bodor, 1984; Bodor, N. et al., 1980(b)) has developed a class of labile quaternary ammonium salts having a general structure depicted in Formula 1. ##STR1##
In this structure, R and R.sub.1 each represent hydrogen, alkyl, or aryl; X is oxygen or sulfur and Y is a halogen. These compounds hydrolyze to yield the parent tertiary amine, an aldehyde (RCHO), a carboxylic acid (R.sub.1 COXH), and HY. Applications of this approach have included the preparation of soft quaternary germicides, antiglaucoma agents, anticholinergic agents, and antitumor agents. (Hammer et al., 1993; Bodor, N. and Kaminski, J., 1980; Bodor, N., 1977).
Vinogradova et al. have studied tertiary amine prodrugs using a variety of tertiary amines of various chemical structures representing different pharmacological classes of drugs (Vinogradova, N. et al., 1980). The general structure of the prodrugs of Vinogradova et al. is shown in Formula II where R is alkyl or acyl and X is a halogen. ##STR2## Another example of a prodrug of a tertiary amine is that of Bogardus et al. having the labile quaternary salt of Formula III, where R represents H, CH.sub.3 or CH.sub.3 CO. (Bogardus, J. et al., 1982). ##STR3##
However, the possible production of a quinone methide intermediate following decomposition may preclude this prodrug from clinical application due to toxicity.
Tercel et al. have proposed the tertiary amine prodrug for the nitrogen mustard anti-cancer agent mechlorethamine shown in Formula IV(a) and (b) Formula IV(a) shows the parent drug mechlorethamine and Formula IV(b) shows the proposed hypoxia-selective tertiary amine prodrug. (Tercel, M., et al., 1993). ##STR4##
The nitrrobenzyl promoiety of the prodrug of mechlorcethamine was designed primarily as a new class of hypoxia-selective cytotoxin. The quaternary nature of the prodrug deactivates the mustard and increases its water solubility. One electron reduction of the nitroaromatic portion causes the release of the reactive aliphatic mustard in cells which are deprived of oxygen, such as those in solid tumors.
Davidson investigated the ability of N-(acyloxyalkyl) pyridinium salts to enhance the solubility of a platelet activating factor antagonist (Davidson, S., et al., 1994). The general structure of these prodrugs is shown in Formula V, where buffer and plasma stability can be adjusted through variations of R.sub.1 and R.sub.2. ##STR5##
The use of a methylene-spaced phosphate group applied to an imide and an alcohol has been reported as a promoiety in two separate reports. Varia and Stella were the first to report on the use of this prodrug strategy when they described a water-soluble phenytion prodrug, 3-(hydroxymethyl)-5,5-diphenylhydantion disodium phosphate ester (Varia, S., et al., 1984(a); Varia, S. et al., 1984(b); Varia, S. et al., 984(c); Varia, S. et al., 1984(d)). This prodrug was shown to be a substrate for alkaline phosphatase, an enzyme ubiquitous to the human body. The prodrug breaks down in the presence of alkaline phosphatase to give the parent drug, formaldehyde, and inorganic phosphate as shown in Reaction Scheme I. ##STR6##
The second use of the promoiety was presented in EP 0 604,910 A1 by Golik et al. The investigators described prodrugs with derivatization on the 2'- and 7-position alcohols of the taxane molecule. The prodrugs were created in an effort to improve the poor aqueous solubility of taxol. This prodrug also degraded in the presence of alkaline phosphatase to give the parent taxane derivative, formaldehyde and inorganic phosphate. However, neither Varia and Stella nor Golik et al. apply this technology to amine drugs.